Small molecule pharmaceuticals have long been the standard in treatment for a variety of diseases, including, but not limited to, cancer. Such small molecule pharmaceuticals are normally administered orally in the form of liquids, pills, capsule and the like or parenterally in the form of injectable or intravenous formulations. While effective in treating a great many conditions, many challenges remain. These include, but are not limited to, controlling the rate of drug delivery, targeting the delivery of the compounds to the desired site of action and maximizing the half-life of the compounds in the circulation. For example, many compounds exhibit decreased efficacy and therapeutic benefit due to metabolism prior to reaching the site of action. In addition, many compounds are relatively insoluble in aqueous solvents, requiring the use of complicated formulations for administration. In some instances, this may limit their usefulness clinically even though they are effective in preclinical studies.
One objective in the field of drug delivery is to preferentially deliver a compound to a desired site of action. Furthermore, an additional objective is control, at least partially, the delivery of the compound once the compound reaches the site of action. Still further, an additional objective is to accomplish one or more of the foregoing objectives with a delivery system that stabilizes the compound when delivered in vivo, extends the half-life of the compound in vivo and aids in solubilizing compounds, particularly those compounds that are insoluble in aqueous solvents.
In order to address the shortcomings in the art, antibody-drug conjugates (ADCs) have been explored. A great deal of research and development has shown that ADCs are effective at providing targeted destruction of cancer cells in animal models as well as in humans (P. D. Senter and E. L. Sievers, Nature Biotechnology, 30, 631-637 (2012); C&EN, Antibody Drug Conjugates, Jun. 18, 2012, pages 12-18; J. D. Thomas, et al., Bioconjugate Chem., 23, 2007-2013 (2012); and references therein). Although this concept had been discussed for many years, the realization of the concept took several decades to fulfill. The first “armed antibody” was not approved until 2011 (P. D. Senter and E. L. Sievers, Nature Biotechnology, 30, 631-637 (2012)). In its most common form one to four molecules of a drug or other compound (referred to here as an “agent”) are coupled to an antibody using linker chemistry designed to release the agent into the tumor mass or into a tumor cell. One limitation of this approach is that insufficient toxin may be attached to the antibody to kill certain tumors, especially when less powerful toxins are used or when there is reduced antigen density present on the tumor cell surface. Also, increasing the number of points of toxin attachment on the antibody may compromise antibody binding capacity and decrease its ability to kill cancer cells. Additionally, this approach can be problematic with compounds that are difficult to solubilize. Finally, some toxins, when attached to antibodies, are so hydrophobic that they are taken up by off-target tissues independent of the binding region of the antibody—thus limiting their effective therapeutic potential.
Another approach is to use a biodegradable polymer such as the polyacetal derived from oxidized dextran (Yurokovetskiy et al, U.S. Pat. No. 8,685,383). In such an approach, the polymer-ADC may contain multiple copies of the agent linked to the polymer backbone with the polymer itself being linked to the antibody. A drug-antibody ratio (DAR) of greater than 1 allows for improved cytotoxicity results when compared to non-targeted polymer drug conjugates alone. Biodegradable polymers, such as the polyacetal above, have the advantage of degrading and thus avoiding accumulation in the body. However, they also have the disadvantage of degrading more quickly than desired, either during preparation or in the body after injection. This approach may lead to premature release of the cytotoxic agent during circulation, thus limiting its effectiveness before it reaches the antigen on the target cell. Secondly, many such polymers, including the polyacetal above, have a biological origin and this can lead to manufacturing challenges related to removing dangerous impurities, and it can increase the risk of adverse reactions when administered to a subject.
An additional approach has been to attach an antibody to a biocompatible polymer (referred to as a polymer-ADC). A simple approach is to attach a linear polymer such as polyethylene glycol (PEG) between the antibody and the drug. This was demonstrated by Riggs-Sauthier et al (US 2014/0088021), where one linear heterobifunctional PEG of either 2 kDa or 20 kDa is first attached to one thiol on the HER2 antibody by maleimide chemistry. The PEG antibody complex is then coupled with one cytotoxic small molecule through an ester linkage. This approach may have significant disadvantages because the ester link is not stable in-vivo and will hydrolyze to release the cytotoxic agent in blood before it reaches the antigen on the target cell. The in vivo efficacy study in this work was not able to demonstrate active targeting of the polymer-ADC when either a 2 kDa or a 20 kDa polymer was used. The efficacy that was demonstrated was likely due to a pharmacokinetic half-life extension of the cytotoxic agent due to the PEG moiety. In addition, the PEG polymer-ADCs lost bioactivity in the cytotoxicity assay when compared to the drug alone. The drug to antibody ratio (DAR) in this scenario is only one, offering no advantage over the non-polymer-ADC approach. The arming of multiple copies of either the drug or the antibody on the linear PEG polymer cannot be achieved with this approach.
In consideration of the foregoing, the field is in need of an ADC, in particular a polymer-ADC, which addresses the limitations described above. The present application provides a solution to these issues by providing a polymer-ADC that is of synthetic manufacture, provides for increased loading (higher DAR values) of the agent onto the targeting antibody, provides for increased half-life of the conjugate in vivo, and does not interfere substantially with the binding activity of the targeting agent (i.e., an antibody). Furthermore, the polymer-ADC conjugates of the present disclosure are readily constructed, and they can provide enhanced solubility of the compound to be delivered. Finally, the polymer-ADC conjugates of the present disclosure do not release drug until they reach the antigen on the target cell and are internalized, where the agent is released following cleavage from the polymer. In this application, HBL-2, MEC-1 and Ramos cells lines (human B-cell lymphoma-derived cell lines) are used as examples.